Ultrasonic neuromodulation by brain stimulation with transcranial ultrasound

Brain stimulation methods are indispensable to the study of brain function. They have also proven effective for treating some neurological disorders. Historically used for medical imaging, ultrasound (US) has recently been shown to be capable of noninvasively stimulating brain activity. Here we provide a general protocol for the stimulation of intact mouse brain circuits using transcranial US, and, using a traditional mouse model of epilepsy, we describe how to use transcranial US to disrupt electrographic seizure activity. The advantages of US for brain stimulation are that it does not necessitate surgery or genetic alteration, but it confers spatial resolutions superior to other noninvasive methods such as transcranial magnetic stimulation. With a basic working knowledge of electrophysiology, and after an initial setup, ultrasonic neuromodulation (UNMOD) can be implemented in less than 1 h. Using the general protocol that we describe, UNMOD can be readily adapted to support a broad range of studies on brain circuit function and dysfunction.

[1]  E. N. Harvey,et al.  THE EFFECT OF HIGH FREQUENCY SOUND WAVES ON HEART MUSCLE AND OTHER IRRITABLE TISSUES , 1929 .

[2]  G. Ludwig,et al.  The Velocity of Sound through Tissues and the Acoustic Impedance of Tissues , 1950 .

[3]  [Experimental epilepsy produced by ultrasonics. I. Semeiological, electroencephalographic and anatomicopathological observations following application of low dosage of ultrasonics on guinea pig encephalon with intact theca]. , 1953, Rivista di patologia nervosa e mentale.

[4]  R.N.Dej.,et al.  Epilepsy and the Functional Anatomy of the Human Brain , 1954, Neurology.

[5]  [Effect of anticonvulsant and neuroplegic drugs on experimental epilepsy induced with ultrasonics]. , 1956, Revue neurologique.

[6]  W. Fry,et al.  Production of reversible changes in the central nervous system by ultrasound. , 1958, Science.

[7]  E. Henneman,et al.  Reversible effects of ultrasound on spinal reflexes. , 1962, Archives of neurology.

[8]  P. P. Lele,et al.  EFFECTS OF ULTRASONIC RADIATION IN EXPERIMENTAL FOCAL EPILEPSY IN THE CAT. , 1964, Experimental neurology.

[9]  W. D. Thompson,et al.  Excitation of pyramidal tract cells by intracortical microstimulation: effective extent of stimulating current. , 1968, Journal of neurophysiology.

[10]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. 3. Mechanisms. , 1972, Electroencephalography and clinical neurophysiology.

[11]  R. Racine Modification of seizure activity by electrical stimulation. I. After-discharge threshold. , 1972, Electroencephalography and clinical neurophysiology.

[12]  J. B. Ranck,et al.  Which elements are excited in electrical stimulation of mammalian central nervous system: A review , 1975, Brain Research.

[13]  E. E. Shchekanov,et al.  The effect of focused ultrasound on the skin and deep nerve structures of man and animal. , 1976, Progress in brain research.

[14]  K R Foster,et al.  Auditory responses in cats produced by pulsed ultrasound. , 1978, The Journal of the Acoustical Society of America.

[15]  A. Barker,et al.  NON-INVASIVE MAGNETIC STIMULATION OF HUMAN MOTOR CORTEX , 1985, The Lancet.

[16]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[17]  L R Gavrilov,et al.  Use of amplitude-modulated focused ultrasound for diagnosis of hearing disorders. , 1988, Ultrasound in medicine & biology.

[18]  L A Crum,et al.  The significance of membrane changes in the safe and effective use of therapeutic and diagnostic ultrasound. , 1989, Physics in medicine and biology.

[19]  H. Wachtel,et al.  Transient modification of nerve excitability in vitro by single ultrasound pulses. , 1990, Biomedical sciences instrumentation.

[20]  H. Wachtel,et al.  Temporally-specific modification of myelinated axon excitability in vitro following a single ultrasound pulse. , 1990, Ultrasound in medicine & biology.

[21]  Patricia C. Rinaldi,et al.  Modification by focused ultrasound pulses of electrically evoked responses from an in vitro hippocampal preparation , 1991, Brain Research.

[22]  K. Türker,et al.  Electromyography: some methodological problems and issues. , 1993, Physical therapy.

[23]  T. Magee,et al.  Auditory phenomena during transcranial Doppler insonation of the basilar artery , 1993, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[24]  Poul Jennum,et al.  Repetitive transcranial magnetic stimulations of the rat effect of acute and chronic stimulations on pentylenetetrazole-induced clonic seizures , 1996, Epilepsy Research.

[25]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[26]  L. R. Price,et al.  Focused ultrasound modifications of neural circuit activity in a mammalian brain. , 1998, Ultrasound in medicine & biology.

[27]  C M Epstein,et al.  Repetitive transcranial magnetic stimulation activates specific regions in rat brain. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  F A Jolesz,et al.  Demonstration of potential noninvasive ultrasound brain therapy through an intact skull. , 1998, Ultrasound in medicine & biology.

[29]  S Meghji,et al.  Effect of ultrasound on the production of IL-8, basic FGF and VEGF. , 1999, Cytokine.

[30]  A T Barker,et al.  The history and basic principles of magnetic nerve stimulation. , 1999, Electroencephalography and clinical neurophysiology. Supplement.

[31]  Louise Poissant Part I , 1996, Leonardo.

[32]  Mark A. Hayner,et al.  Numerical analysis of ultrasonic transmission and absorption of oblique plane waves through the human skull. , 2001, Journal of the Acoustical Society of America.

[33]  L. Cohen,et al.  Transcranial magnetic stimulation in the rat , 2001, Experimental Brain Research.

[34]  G T Clement,et al.  A non-invasive method for focusing ultrasound through the human skull. , 2002, Physics in medicine and biology.

[35]  P. Whelan,et al.  Electromyogram recordings from freely moving animals. , 2003, Methods.

[36]  H. Möller,et al.  Repetitive Transcranial Magnetic Stimulation , 2003, CNS drugs.

[37]  Diane Dalecki,et al.  Mechanical bioeffects of ultrasound. , 2004, Annual review of biomedical engineering.

[38]  Natalia Vykhodtseva,et al.  500‐element ultrasound phased array system for noninvasive focal surgery of the brain: A preliminary rabbit study with ex vivo human skulls , 2004, Magnetic resonance in medicine.

[39]  O. Altland,et al.  Low‐intensity ultrasound increases endothelial cell nitric oxide synthase activity and nitric oxide synthesis , 2004, Journal of thrombosis and haemostasis : JTH.

[40]  M. Ueda,et al.  Ultrasound enhances transforming growth factor beta-mediated chondrocyte differentiation of human mesenchymal stem cells. , 2004, Tissue engineering.

[41]  P. Tsui,et al.  In vitro effects of ultrasound with different energies on the conduction properties of neural tissue. , 2005, Ultrasonics.

[42]  W. Theodore Brain stimulation for epilepsy , 2005, Nature Clinical Practice Neurology.

[43]  Ferenc A. Jolesz,et al.  Local and reversible blood–brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications , 2005, NeuroImage.

[44]  T. Heimburg,et al.  On soliton propagation in biomembranes and nerves. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[45]  E. J. Tehovnik,et al.  Mapping Cortical Activity Elicited with Electrical Microstimulation Using fMRI in the Macaque , 2005, Neuron.

[46]  E. Sant'anna,et al.  Effect of low intensity pulsed ultrasound and BMP‐2 on rat bone marrow stromal cell gene expression , 2005, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[47]  A. Virdi,et al.  Early gene response to low-intensity pulsed ultrasound in rat osteoblastic cells. , 2005, Ultrasound in medicine & biology.

[48]  K. Hynynen,et al.  Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound. , 2006, Biochemical and biophysical research communications.

[49]  Shahram Vaezy,et al.  Image-Guided High-Intensity Focused Ultrasound for Conduction Block of Peripheral Nerves , 2006, Annals of Biomedical Engineering.

[50]  Gregory T. Clement,et al.  Longitudinal and shear mode ultrasound propagation in human skull bone. , 2006, Ultrasound in medicine & biology.

[51]  Mark E. Schafer,et al.  From the Cover : Prenatal exposure to ultrasound waves impacts neuronal migration in mice , 2006 .

[52]  M. Nitsche,et al.  Anticonvulsant Effects of Transcranial Direct‐current Stimulation (tDCS) in the Rat Cortical Ramp Model of Focal Epilepsy , 2006, Epilepsia.

[53]  Kullervo Hynynen,et al.  Pre-clinical testing of a phased array ultrasound system for MRI-guided noninvasive surgery of the brain--a primate study. , 2006, European journal of radiology.

[54]  M. Morrell Brain stimulation for epilepsy: can scheduled or responsive neurostimulation stop seizures? , 2006, Current opinion in neurology.

[55]  K Hynynen,et al.  Local frequency dependence in transcranial ultrasound transmission. , 2006, Physics in medicine and biology.

[56]  Dirk Van Roost,et al.  Deep Brain Stimulation in Patients with Refractory Temporal Lobe Epilepsy , 2007, Epilepsia.

[57]  Á. Pascual-Leone,et al.  Noninvasive human brain stimulation. , 2007, Annual review of biomedical engineering.

[58]  Feng Zhang,et al.  An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology , 2007, Journal of neural engineering.

[59]  Gail ter Haar,et al.  Therapeutic applications of ultrasound. , 2007, Progress in biophysics and molecular biology.

[60]  L. Claes,et al.  The enhancement of bone regeneration by ultrasound. , 2007, Progress in biophysics and molecular biology.

[61]  W. H. Jordan,et al.  Mesial Temporal Lobe Epilepsy: Pathogenesis, Induced Rodent Models and Lesions , 2007, Toxicologic pathology.

[62]  Timothy G Leighton,et al.  What is ultrasound? , 2007, Progress in biophysics and molecular biology.

[63]  M. Hallett Transcranial Magnetic Stimulation: A Primer , 2007, Neuron.

[64]  D. Burke,et al.  Use of magnetic stimulation to elicit motor evoked potentials, somatosensory evoked potentials, and H-reflexes in non-sedated rodents , 2007, Journal of Neuroscience Methods.

[65]  Á. Pascual-Leone,et al.  Technology Insight: noninvasive brain stimulation in neurology—perspectives on the therapeutic potential of rTMS and tDCS , 2007, Nature Clinical Practice Neurology.

[66]  Gregory T. Clement,et al.  Clinical applications of focused ultrasound—The brain , 2007, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[67]  M. Kringelbach,et al.  Translational principles of deep brain stimulation , 2007, Nature Reviews Neuroscience.

[68]  Jaung-Geng Lin,et al.  Ultrasound induces cyclooxygenase-2 expression through integrin, integrin-linked kinase, Akt, NF-kappaB and p300 pathway in human chondrocytes. , 2007, Cellular signalling.

[69]  J. Aimonetti,et al.  Evaluation of transcranial magnetic stimulation for investigating transmission in descending motor tracts in the rat , 2007, The European journal of neuroscience.

[70]  W. O’Brien Ultrasound-biophysics mechanisms. , 2007, Progress in biophysics and molecular biology.

[71]  Yusuf Tufail,et al.  Remote Excitation of Neuronal Circuits Using Low-Intensity, Low-Frequency Ultrasound , 2008, PloS one.

[72]  G. Fritsch,et al.  Electric excitability of the cerebrum (Über die elektrische Erregbarkeit des Grosshirns) , 2009, Epilepsy & Behavior.

[73]  A. Wixforth,et al.  Wave propagation in lipid monolayers. , 2009, Biophysical journal.

[74]  Warren M Grill,et al.  Implanted neural interfaces: biochallenges and engineered solutions. , 2009, Annual review of biomedical engineering.

[75]  T. Murphy,et al.  Automated light-based mapping of motor cortex by photoactivation of channelrhodopsin-2 transgenic mice , 2009, Nature Methods.

[76]  O. Devinsky,et al.  The excitable cerebral cortex: Fritsch G, Hitzig E. Über die elektrische Erregbarkeit des Grosshirns. Arch Anat Physiol Wissen 1870;37:300–32. , 2009, Epilepsy & Behavior.

[77]  Philippe Kahane,et al.  Manipulating the epileptic brain using stimulation: a review of experimental and clinical studies. , 2009, Epileptic disorders : international epilepsy journal with videotape.

[78]  J. Prudic,et al.  Electroconvulsive Therapy: Part I. A Perspective on the Evolution and Current Practice of ECT , 2009, Journal of psychiatric practice.

[79]  R. Reid,et al.  Direct Activation of Sparse, Distributed Populations of Cortical Neurons by Electrical Microstimulation , 2009, Neuron.

[80]  N. Fang,et al.  Focusing ultrasound with an acoustic metamaterial network. , 2009, Physical review letters.

[81]  G. Miesenböck,et al.  The Optogenetic Catechism , 2009, Science.

[82]  Xiaobo Yin,et al.  Experimental demonstration of an acoustic magnifying hyperlens. , 2009, Nature materials.

[83]  A. Morel,et al.  High‐intensity focused ultrasound for noninvasive functional neurosurgery , 2009, Annals of neurology.

[84]  T. Heimburg,et al.  Lipid ion channels. , 2010, Biophysical chemistry.

[85]  Byoung-Kyong Min,et al.  Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity , 2011, BMC Neuroscience.

[86]  Barbara C Jobst,et al.  Electrical Stimulation in Epilepsy: Vagus Nerve and Brain Stimulation , 2010, Current treatment options in neurology.

[87]  S. Tillery,et al.  Transcranial Pulsed Ultrasound Stimulates Intact Brain Circuits , 2010, Neuron.

[88]  L. Leocani,et al.  Brain transcranial direct current stimulation modulates motor excitability in mice , 2010, The European journal of neuroscience.

[89]  J-F Aubry,et al.  MR-guided transcranial brain HIFU in small animal models , 2010, Physics in medicine and biology.

[90]  Clement Hamani,et al.  The history and future of deep brain stimulation , 2011, Neurotherapeutics.

[91]  Jong-Hwan Lee,et al.  Focused ultrasound modulates region-specific brain activity , 2011, NeuroImage.